“Female mice and estrogen-treated male mice showed greater clearance of bacteria from the lungs and less acute inflammation (neutrophil influx) compared to normal or sham-treated males 24 hours after inoculation of Streptococcus pneumoniae,” wrote the authors. As a primary goal, the team sought to show high female resistance to pneumococcal pneumonia infection of the upper airway using mice infected with the bacterium. Interestingly, although the female mice showed a lesser bacterial burden 24 hours after infection, they had a greater bacterial load than males five minutes after infection.

The team was then interested in an explanation for this phenomenon and turned to alveolar macrophages, a type of cell that “eats” and kills bacteria in the lungs. Although alveolar macrophages from female and male mice showed no difference in binding and internalization of bacteria, the cells from female mice had a greater killing capacity for internalized bacteria.

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A reason for this greater killing capacity was nitric oxide synthase-3 (NOS3) activity. Inhibiting NOS3 in alveolar macrophages grown in a petri dish diminished the female advantage in killing capacity. Inhibition was achieved using nitro-l-arginine, a non-selective NOS blocker.

Since it appeared NOS3 had protective effects on the cells, the team was interested in enhancing killing capacity by delivering molecules that would boost NOS3 activity. Aerosolized estrogen enhanced bacterial clearance in male mice. Looking to support their finding, the team conducted an analysis of female pneumonia patient hospital records and found estrogen-replacement therapy reduced the risk for contracting pneumonia that required hospitalization.

Two additional means of boosting NOS3 included statins and the small molecule AVE3085. Either of these molecules enhanced macrophage killing capacity and was protective against bacterial infection in mice. The team concluded that these molecules “could well benefit patients who are identified to be at high risk of secondary pneumonia, e.g. hospitalized individuals with severe seasonal or pandemic influenza,” as these patients commonly contract pneumonia during hospitalization for the flu. These interventions could serve a similar purpose as that of Pulmotect, Inc.’s leading pipeline product, PUL-042, which is considered an immune-boosting drug to protect against lung infections.

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